Multiple mutations of IFITM3 are associated with COVID-19 susceptibilityregulation function of IFITM3 in COVID-19
Authors: Hongzhe Guo, Tianyi Zhao
Journal: Journal of Infection (2023)

Individuals have different symptoms of COVID-19 infection, which is not only caused by environmental and socioeconomic factors. Many studies have pointed out that it is closely related to genetic factors. We read with interest the publication by Li et al.1Li Y. Wei L. He L. Sun J. Liu N. Interferon-induced transmembrane protein 3 gene polymorphisms are associated with COVID-19 susceptibility and severity: a meta-analysis.J Infect. 2022; 84: 825-833Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar reporting the relationship between Interferon-induced transmembrane protein 3 gene (IFIM3) polymorphisms and susceptibility and severity of COVID-19. Through a genotype study of 1989 samples, they found that the rs12252 of IFIM3 polymorphism was associated with COVID-19 susceptibility and severity, while rs34481144 was not. However, they only compared the genotypic differences of controls, mild and severe by statistical means, thus finding out the SNP (rs12252) related to the susceptibility and severity of COVID-19, and did not reveal the relationship between the function of rs12252 and the susceptibility and severity. Therefore, we try to explore the biological function of rs12252 associated with COVID-19 through a variety of large-scale sequencing data, and continue to explore whether rs34481144 is related to the susceptibility and severity of COVID-19. First, the expression quantitative trait loci (eQTLs) disclosed by GTEx2GTEx ConsortiumThe GTEx Consortium atlas of genetic regulatory effects across human tissues.Science. 2020; 369: 1318-1330Crossref PubMed Google Scholar showed that rs12252 regulated the expression of PGGHG and RP11–326C3.13 in lung tissue (sample size=515). The P-value is 2.7e-5 and 3.0e-5 respectively, which means rs12252 has a strong regulatory function on the expression of PGGHG and RP11–326C3.13 in lung tissue (Fig. 1(A),(B)). Furthermore, through 9 lung samples single-cell RNA-seq data from COVID-19 patients, PGGHG showed significantly differential expression between COVID-19 patients and controls.3Wu M. Chen Y. Xia H. Wang C. Tan C.Y. Cai X. et al.Transcriptional and proteomic insights into the host response in fatal COVID-19 cases.Proc Natl Acad Sci. 2020; 117: 28336-28343Crossref PubMed Scopus (121) Google Scholar The log2 fold change is −1.5 with P-value 4.6144e-4. However, no evidence has shown the relationship between RP11–326C3.13 and COVID-19. This suggests that the regulation of rs12252 on PGGHG can significantly affect the susceptibility to COVID-19. We also investigated the regulatory relationship of rs34481144 in lung tissue. Seven genes expression can be regulated by rs34481144 with low P-value. Among these genes, PGGHG, IFITM1 and IFITM3 are reported to be related to COVID-19. Multigroup mouse experiments confirmed that IFITM1 had significant abnormal expression under the infection of COVID-19 homologous virus. Zornetzer et al.4Zornetzer G.A. Frieman M.B. Rosenzweig E. Korth M.J. Page C. Baric R.S. et al.Transcriptomic analysis reveals a mechanism for a prefibrotic phenotype in STAT1 knockout mice during severe acute respiratory syndrome coronavirus infection.J Virol. 2010; 84: 11297-11309Crossref PubMed Scopus (38) Google Scholar compared the gene expression of STAT1 knockout mice during severe acute respiratory syndrome coronavirus infection with normal mice and found a log2FC of 2.5 for IFITM1 with p-value of 2.8163e-5. Xiong et al.,5Xiong H. Morrison J. Ferris M.T. Gralinski L.E. Whitmore A.C. Green R. et al.Genomic profiling of collaborative cross founder mice infected with respiratory viruses reveals novel transcripts and infection-related strain-specific gene and isoform expression.Genes Genomes Genet. 2014; 4: 1429-1444Google Scholar Yoshikawa et al.6Yoshikawa T. Hill T.E. Yoshikawa N. Popov V.L. Galindo C.L. Garner H.R. et al.Dynamic innate immune responses of human bronchial epithelial cells to severe acute respiratory syndrome-associated coronavirus infection.PLoS One. 2010; 5e8729Crossref Scopus (129) Google Scholar and Regla-Nava et al.7Regla-Nava J.A. Nieto-Torres J.L. Jimenez-Guardeño J.M. Fernandez-Delgado R. Fett C. Castaño-Rodríguez C. et al.Severe acute respiratory syndrome coronaviruses with mutations in the E protein are attenuated and promising vaccine candidates.J Virol. 2015; 89: 3870-3887Crossref PubMed Scopus (103) Google Scholar all compared the gene expression between SARS coronavirus MA15 mice and normal mice, and their experimental data showed that IFITM1 had a significant difference in expression. The log2FC are 1.9 (P-value=2.6e-6), 1.2 (P-value=8.68e-7) and 1.7 (P-value=1.9e-2) respectively. In addition, IFITM1 also showed differential expression between mice with SARS-CoV-MA15 and wild types in Regla-Nava et al. study.7Regla-Nava J.A. Nieto-Torres J.L. Jimenez-Guardeño J.M. Fernandez-Delgado R. Fett C. Castaño-Rodríguez C. et al.Severe acute respiratory syndrome coronaviruses with mutations in the E protein are attenuated and promising vaccine candidates.J Virol. 2015; 89: 3870-3887Crossref PubMed Scopus (103) Google Scholar In addition, many studies have confirmed that the down-regulation of IFITM1 and the up-regulation of IFITM3 are significantly related to the morbidity and mortality of COVID-19.8Dowran R. Nabavi S.F. Habtemariam S. Banach M. Shahmohamadnejad S. Cismaru C.A. et al.Various interferon (IFN)-inducible transmembrane (IFITM) proteins for COVID-19, is there a role for the combination of mycophenolic acid and interferon?.Biochimie. 2020; 177: 50-52Crossref PubMed Scopus (6) Google Scholar, 9Regino-Zamarripa N.E. Ramírez-Martínez G. Jiménez-Álvarez L.A. Cruz-Lagunas A. Gómez-García I.A. Ignacio-Cortés S. et al.Differential leukocyte expression of IFITM1 and IFITM3 in patients with severe pandemic influenza A (H1N1) and COVID-19.J Interferon. 2022; 42: 430-443Crossref Scopus (5) Google Scholar, 10Sinha S. Rosin N.L. Arora R. Labit E. Jaffer A. Cao L. et al.Dexamethasone modulates immature neutrophils and interferon programming in severe COVID-19.Nat Med. 2022; 28: 201-211Crossref PubMed Scopus (106) Google Scholar The expression of multiple genes regulated by rs34481144 is significantly related to the susceptibility and severity of COVID-19. Therefore, its regulatory role in COVID-19 cannot be ignored. Overall, consistent with Li et al., rs12252 is significantly related to the susceptibility and severity of COVID-19. However, through the analysis of multiple sets of data, we believe that the regulation of rs12252 on PGGHG is the main factor related to COVID-19. At the same time, we infer that rs34481144 plays an important role in COVID-19 by regulating the expression of PGGHG, IFITM1 and IFITM3 (Table 1).Table 1Regulation information of rs34481144 and rs12252 in lung.GeneSNPP-valueEffect sizeTissueRP11–326C3.11rs344811446.20E-07-0.23LungIFITM3rs344811447.70E-07-0.11LungIFITM1rs344811448.6E-060.14LungPGGHGrs344811440.0000660.17LungRP11–326C3.15rs344811444.40E-070.23LungRP11–326C3.12rs344811441.60E-080.27LungRP11–326C3.13rs344811442.90E-160.45LungPGGHGrs122520.000022-0.36LungRP11–326C3.2rs122520.000053-0.35Lung Open table in a new tab None. This work has been supported by Natural Science Foundation of China (62102116, 62202125); Interdisciplinary Research Foundation of HIT.